with other molecules (such as so 斜 斜 ion by hete he mac omolcecararchitecrc5dcsigneddiTcny and macrop 梦 gnition).The binding kinetics s and ng alternative Figure 11.The heart of the configurational biomimetic includes a post-crosslinking re ed int the ork afte ned an e recognition in s0 e areas(C)A slinking in di sol S. thin the polym ding sol free energies ciated elastic nature net e designed in a with re ve or cel gels via tether ing betw hains (that i via op and pleted edures.The use of imprinted highly cr (Peppas and Huang.2002)have of low cognition n (Pepp) 0 the ntr e of quiresa different methodolo ein s of ch ins formed c segment that ns are ed of cspondipgincTcasCinfpctionalmonomcrmolccularWcieb The size below a certain limit would produce a very restricted net work for template diffusion and rebinding. December 2003 Vol.49.No.12 AIChE Journal Figure 11. The heart of the configurational biomimetic process. Ž . A Appropriate crosslinking to functional monomer size. Ž. Ž . B An increase in crosslinker molecular weight linear size without a change in functional monomer size. Note possi￾ble loss of effective recognition in some areas. C A corre- Ž . sponding increase in functional monomer molecular weight Ž . linear size compared to crosslinking monomer. delivery are intelligent, stimuli-responsive gel systems that ex￾hibit oscillatory swelling and, hence, modulate release in re￾sponse to pH, temperature, ionic strength, electric fields, or specific analyte concentration differences Byrne et al., 2002 . Ž . In these systems, release can be designed to occur via spe￾cific sites adhesive or cell-receptor specific gels via tethered Ž chains from the hydrogel surface . Currently, most analyte- . sensitive gels are not entirely artificial and require a protein within the polymer matrix as the sensingractivation mecha￾nism Byrne et al., 2002 . The inclusion of proteins, lectins, Ž . and other compounds Figure 10 introduces immunogenic Ž . targets within these gels, as well as more constrained process￾ing procedures. The use of imprinted highly crosslinked gels as the sensingractivation mechanism could lead to a variety of new, robust bimolecular sensing hydrogel networks for drug delivery Peppas and Huang, 2002 . Ž . Since hydrogels swell significantly and contain large amounts of a hydrophilic solvent within a thermodynamically Ž favorable solvent, the macromolecular network will solvate and the network will expand , imprinting in hydrogels re- . quires a different methodology. However, there are numer￾ous examples of such systems in nature. Proteins are het￾eropolymers that contain both flexible and rigid areas, which have diverse dynamic binding functions. A protein can have side chain flexibility, amino acid segment mobility, and do￾main flexibility between various amino acid chain domains Ž . Huber and Bennett, 1983 . Since proteins are composed of a linear sequence or sequences of amino acids with each Ž . amino acid having a unique residue group such as hy- Ž drophilic or hydrophobic, varying electrostatic properties, hy￾drogen bond donor or acceptor , it is this sequence that dic- . tates the conformation of the final protein. The direct inter￾actions of these groups with the water, with each other, and with other molecules such as cofactors, chaperones, and so Ž on influence the folding of a protein into a stable 3-D ar- . rangement. Theoretical analysis of protein folding and recog￾nition by heteropolymers is the subject of a number of re￾views Jozefowicz and Jozefonvicz, 1997; Pande et al., 2000; Ž Chakraborty, 2001; Shea and Brooks, 2001 .. The macromolecular architecture is designed differently than more traditional dense networks and must include a spatially varying crosslinking density micro- and macrop- Ž orous regions . Density fluctuations in the polymer network . create regions or microgels of localized higher crosslinking, which contain an effective imprinting structure and proper rigidity to produce adequate specificity areas or patches of Ž recognition . The binding kinetics and mass transfer of this . design can be enhanced compared to known dense gels mass Ž transfer is slow and rebinding percentage is low as templates inherently are trapped within the matrix . However, analyte . binding capacity is reduced on a per gel mass or volume basis Ž . Peppas and Huang, 2002 . One promising alternative includes a post-crosslinking re￾action, either between excess functional monomers on oppo￾site macromolecular chains or via other monomers intro￾duced into the network after the gel is formed and imprint is rebound. Since polymerization occurs within a solvent as Ž crosslinking in dilute polymer solutions minimizes physical entanglements and heterogeneity within the polymer network Ž . Scott and Peppas, 1999 , matching polymerization and re￾binding solvents in terms of dielectric constant, polarity, pro￾tic nature, and so on or keeping the original solvent when Ž rebinding will reduce differences in swelling behavior Gibbs . Ž free energies associated with the elastic nature of the net￾work and the energy of mixing . In these cases, the network . can be designed in a less dense manner with recognition oc￾curring between flexible functionalized chains that is, longer Ž and higher molecular weight stabilized by additional post- . crosslinking and post-stabilizing reactions either via opposite chains or within the functional monomer chain itself and a macromolecular chain. To date, little work has been com￾pleted on low crosslinked imprinted systems except for some recent work Peppas and Huang, 2002; Byrne et al., 2002 . Ž . These methods Peppas and Huang, 2002 have produced Ž . a new generation of low crosslinking recognition networks. In designing the macromolecular architecture with respect to monomer type and composition, as the molecular weight of the crosslinking monomer is increased, the length of the functional monomer or monomers increases accordingly to avoid loss of possible binding regimes irrespective of swelling or shrinking phenomena Figure 13 . This mainly deals with Ž . polymerization kinetics and the nature of the chains formed during polymerization, which influence the network morphol￾ogy on a molecular level. With high crosslinking monomer ratios, the types of chains formed consist of primary copoly￾mer chains of crosslinker and functional monomer and other secondary chains of crosslinking monomer that connect each macromer unit. This is a possible reason why investigators have seen marginal success in imprinting a given analyte by increasing the molecular weight of crosslinker without a cor￾responding increase in functional monomer molecular weight Ž . linear size . Similarly, decreasing the crosslinker molecular size below a certain limit would produce a very restricted net￾work for template diffusion and rebinding. 3000 December 2003 Vol. 49, No. 12 AIChE Journal